JPH10259129A - Arterialization inhibitor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new compound capable of remarkably inhibiting proliferation of human capillary endothelial cell and extremely useful as an arterialization inhibitor. SOLUTION: This compound is a 2-acylaminobenzamide derivative of formula I R<1> is H, a halogen, etc.; R<2> and R<3> are each H, a lower alkyl, etc.; B is N(R<4> )(R<5> ) (R<4> and R<5> are each H, a lower alkyl, etc.), NH-(CH2 )n -A-R<6> [A is a single bond, etc.; R<6> is a substitutable amino; (n) is 2-6]} or its salt, e.g. (E)-2-(3,4-dimethoxycinnamoylamino)benzamide. The compound of formula I is obtained by reacting a carboxylic acid derivative of formula II (R<10> is H, a halogen, etc.) or its reactive functional derivative such as its acid halide or active ester with a 2-acylaminobenzamide derivative, etc., of formula III [B<0> is N(R<4> )(R<5> ), etc.] and a dehydrating agent or a condensation agent in an inert solvent in the presence of a base and as necessary, eliminating a protective group and hydrolyzing the reaction product.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a pharmaceutical composition useful as an angiogenesis inhibitor.

More specifically, the present invention provides a compound represented by the general formula

[0003]

Embedded image

[Wherein R ¹ is a hydrogen atom, a halogen atom,
A hydroxyl group, a lower alkyl group, a lower alkoxy group, a hydroxy lower alkoxy group, a cycloalkyl alkoxy group, an aralkyloxy group, a lower acyl group, a nitro group, a cyano group, an amino group which may be mono- or di-substituted with a lower alkyl group, A carboxyl group, a lower alkoxycarbonyl group or a lower alkylsulfonyl group, wherein R ² and R ³ may be the same or different and are each a hydrogen atom or a lower alkoxy group, or both together via an oxygen atom; A lower alkylene group may be formed, and B is a group represented by the general formula

[0005] ^{-N (R 4) (R 5} )

Wherein R ⁴ and R ⁵ may be the same or different and each is a hydrogen atom, a lower alkyl group, a cycloalkylalkyl group or an aralkyl group;

-NH- (CH ₂ ) _n -A R ⁶

[Wherein A is a single bond, a general formula -O- (CH ₂ ) _m-

Wherein m is an integer of 2 to 6 or a group represented by the general formula:

-N (R ⁷ ) (CH ₂ ) _p-

Wherein R ⁷ is a hydrogen atom or a lower alkyl group which may have a hydroxyl group as a substituent or an amino group which may be mono- or di-substituted with a lower alkyl group, and p is 2 to Which is an integer of 6)
R ⁶ is a hydroxyl group or an amino group which may be mono- or di-substituted with a lower alkyl group, and n is an integer of 2 to 6], and may have a carboxyl group as a substituent. Which is a good arylamino group or a hydroxyamino group), or a pharmacologically acceptable salt thereof as an active ingredient. And therapeutic agents.

[0012] The diseases relating to angiogenesis include various diseases caused by angiogenesis as one of the causes thereof, for example, rheumatoid arthritis, psoriasis, edema sclerosis, diabetic retinopathy, premature infants Retinopathy, sickle cell retinopathy, retinal vein occlusion, angiogenesis associated with corneal transplantation or cataract surgery, neovascular glaucoma, iris rubeosis, senile discoid macular degeneration, various tumors, atherosclerosis Abnormal capillary networks of the monoadventitia, angiogenesis in the cornea due to long-term wearing of contact lenses, and the like.

[0013]

BACKGROUND OF THE INVENTION Angiogenesis generally involves digestion and destruction of the basement membrane of blood vessels by proteases, migration and proliferation of vascular endothelial cells, formation of a lumen by differentiation of vascular endothelial cells, and reconstitution of blood vessels. It is a phenomenon. Angiogenesis occurs physiologically during luteal formation and placental formation, and under pathological conditions, it appears in the above-mentioned diseases. For example, in retinopathy, the retinal tissue intervening between the existing basement membrane around the retinal vessels and the vitreous is first destroyed,
Next, the vascular endothelial cells that make up the existing blood vessels migrate from the gap of the destruction site of the retinal tissue, the vascular endothelial cells proliferate so as to fill the gap between the migrated vascular endothelial cells, and then the vascular endothelial cells migrated to the retinal vitreous body Angiogenesis progresses by reconstituting blood vessels.

Angiogenesis is related to various diseases, for example, it is deeply involved in the onset or progression of the above diseases. Therefore, for the prevention or treatment of these diseases,
Intensive research has been actively pursued to search for substances that inhibit angiogenesis. For example, examples of angiogenesis inhibitors include a microbial metabolite fumagillin analog having an inhibitory action on vascular endothelial cells, a tetracycline antibiotic having an action of inhibiting collagenase activity, and binding of a heparin-binding angiogenic factor to a receptor. Microorganism-derived D with inhibitory action
-Drugs such as gluco-galactan sulfate are known. However, it is not disclosed at all that the 2-acylaminobenzamide derivative represented by the general formula (I) suppresses the proliferation of capillary endothelial cells, and it is completely known that it is useful as an angiogenesis inhibitor. Not.

[0015]

At present, there are no clinically satisfactory drugs as angiogenesis inhibitors yet, and there is no sufficient treatment for the above-mentioned diseases relating to angiogenesis. Especially in diabetic retinopathy, regression of new blood vessels is not observed unless surgical treatment is performed, and visual impairment due to bleeding from the new blood vessels is a problem, so it is excellent for angiogenesis There is a great need for the development of effective drugs. In contrast, an object of the present invention is to provide a novel angiogenesis inhibitor that suppresses angiogenesis.

[0016]

Means for Solving the Problems The present inventors have conducted intensive studies to find a compound having an inhibitory effect on angiogenesis. As a result, a 2-acylaminobenzamide derivative represented by the above general formula (I) was converted to a human. The present inventors have found that they have an action of remarkably suppressing the proliferation of capillary endothelial cells, and have found that they are extremely useful as an angiogenesis inhibitor, leading to the present invention.

[0017]

BEST MODE FOR CARRYING OUT THE INVENTION

[0018]

Embedded image

[Wherein R ¹ is a hydrogen atom, a halogen atom,
A hydroxyl group, a lower alkyl group, a lower alkoxy group, a hydroxy lower alkoxy group, a cycloalkyl alkoxy group, an aralkyloxy group, a lower acyl group, a nitro group, a cyano group, an amino group which may be mono- or di-substituted with a lower alkyl group, A carboxyl group, a lower alkoxycarbonyl group or a lower alkylsulfonyl group, wherein R ² and R ³ may be the same or different and are each a hydrogen atom or a lower alkoxy group, or both together via an oxygen atom; A lower alkylene group may be formed, and B is a group represented by the general formula

-N (R ⁴ ) (R ⁵ )

Wherein R ⁴ and R ⁵ may be the same or different and each is a hydrogen atom, a lower alkyl group, a cycloalkylalkyl group or an aralkyl group;

-NH- (CH ₂ ) _n -A R ⁶

[A in the formula is a single bond, a general formula

-O- (CH ₂ ) _m-

Wherein m is an integer of 2 to 6 or a general formula

-N (R ⁷ ) (CH ₂ ) _p-

(Wherein R ⁷ is a hydrogen atom or a lower alkyl group which may have a hydroxyl group as a substituent or an amino group which may be mono- or di-substituted with a lower alkyl group, and p is 2 to Which is an integer of 6)
R ⁶ is a hydroxyl group or an amino group which may be mono- or di-substituted with a lower alkyl group, and n is an integer of 2 to 6], and may have a carboxyl group as a substituent. Which is a good arylamino group or a hydroxyamino group) or a pharmacologically acceptable salt thereof as an active ingredient for the prevention and treatment of angiogenesis-related diseases. It is.

In the compound represented by the formula (I), the lower alkyl group means a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group,
c-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, tert-pentyl group,
A straight or branched alkyl group having 1 to 6 carbon atoms, such as a hexyl group, refers to a lower alkoxy group. A lower alkoxy group is a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, or a sec-butoxy group. Group, te
The term refers to a linear or branched alkoxy group having 1 to 6 carbon atoms such as an rt-butoxy group, a pentyloxy group, an isopentyloxy group, a neopentyloxy group, a tert-pentyloxy group, and a hexyloxy group.

The lower alkoxycarbonyl group includes methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl,
Pentyloxycarbonyl group, isopentyloxycarbonyl group, neopentyloxycarbonyl group, tert
-Refers to a linear or branched alkoxycarbonyl group having 2 to 7 carbon atoms, such as a pentyloxycarbonyl group and a hexyloxycarbonyl group.

The aryl group refers to an aromatic hydrocarbon group such as a phenyl group or a naphthyl group, the aralkyl group refers to the lower alkyl group substituted by the aryl group, and the aralkyloxy group refers to the aryl group. A lower alkoxy group substituted with a cycloalkyl group;
Refers to a 7-membered cyclic alkyl group, cycloalkylalkyl group refers to the lower alkyl group substituted with the cycloalkyl group, and cycloalkylalkoxy group refers to the lower alkoxy group substituted with the cycloalkyl group. Say.

The halogen atom is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and the lower acyl group is a straight or branched C2-C2 group such as an acetyl group, a propionyl group and a butyryl group. And a lower alkylsulfonyl group means a linear or branched alkylsulfonyl group having 1 to 6 carbon atoms such as a methanesulfonyl group and an ethanesulfonyl group.

The lower alkylene group via an oxygen atom means an alkylene group having 1 to 6 carbon atoms containing an oxygen atom, such as a methylenedioxy group and an ethylenedioxy group.

The present inventors have found that in an in vitro angiogenesis inhibitory test using human capillary endothelial cells, the 2-acylaminobenzamide derivative represented by the above general formula (I) was significantly different from human capillary blood vessels. It was confirmed that the proliferation of endothelial cells was suppressed.

As described above, the 2-acylaminobenzamide derivative represented by the general formula (I) has an excellent endothelial cell growth inhibitory effect in human capillaries, and is useful as an angiogenesis inhibitor. Which is a very useful compound as an agent for preventing and treating diseases relating to angiogenesis.

Accordingly, 2-
By using an acylaminobenzamide derivative as an active ingredient, a pharmaceutical composition useful as an angiogenesis inhibitor can be produced.

The 2-acylaminobenzamide derivatives represented by the above general formula (I) and their pharmacologically acceptable salts, which are the active ingredients, are partially known compounds, and their production methods are variously known. (For example, Egypt. JC
hem. , Vol. 28, No. 3, pp. 235-238 (19
1985), JP-A-47-2927, JP-A-63-29
5543, JP-A-63-295544, JP-A-1-
26543, Indian J. et al. Chem. , 13
Vol. 4, No. 326-328 (1975), Bu
ll. Trav. Soc. Pharm. Lyon, 17
Vol. 4, No. 143-148 (1973), U.S.A. A.
R. Chem. 13, Vol. 4, No. 4, pp. 379-390 (1970); Chem. U. A. R. , 12
Vol. 1, No. 57-68 (1969), U.S. Patent No. 3,192,214, British Patent Publication No. 1099982.
No. J. Med. Chem. , Vol. 9, No. 16, 809-
812 (1966); Med. Che
m. , Vol. 12, No. 1, pp. 164-166 (1969)
Year), J.M. Chem. Soc. Rev., 4420-4421 (1956), Rev. Room. Chim. ,
Vol. 22, No. 8, pp. 1217 to 1223 (1977)
)), These methods described in the literature or methods similar thereto, or by combining other known methods.

For example, the compound represented by the general formula (I)

[0038]

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(Wherein R ¹⁰ is a hydrogen atom, a halogen atom, a hydroxyl group having a protecting group, a lower alkyl group, a lower alkoxy group, a hydroxy lower alkoxy group having a protecting group, a cycloalkylalkoxy group, an aralkyloxy group, a lower acyl group) Group, nitro group, cyano group, mono-lower alkyl-substituted amino group having a protecting group, di-lower alkyl-substituted amino group, lower alkoxycarbonyl group or lower alkylsulfonyl group, wherein R ² and R ³ are as defined above. And a reactive functional derivative such as an acid halide or an active ester thereof represented by the general formula:

[0040]

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[B ⁰ in the formula is a general formula

-N (R ⁴ ) (R ⁵ )

Wherein R ⁴ and R ⁵ have the same meanings as described above;

-NH- (CH ₂ ) _n -A ⁰ -R ⁸

Wherein A ⁰ is a single bond, a general formula

-O- (CH ₂ ) _m-

Wherein m has the same meaning as described above, or a group represented by the general formula:

-N (R ⁹ ) (CH ₂ ) _p-

(In the formula, R ⁹ may have a hydroxyl group, a mono-lower-alkyl-substituted amino group or a di-lower-alkyl-substituted amino group having a protective group as a protective group or a substituent for an amino group. A lower alkyl group, p
Has the same meaning as described above), and R ⁸ is a hydroxyl group, an amino group which may be mono-lower alkyl-substituted or a di-lower alkyl-substituted amino group having a protecting group, and n is as defined above. Having the same meaning], an arylamino group or a hydroxyamino group optionally having a carboxyl group as a substituent]
An acylaminobenzamide derivative or a closed form thereof [2- (2-aminophenyl) -3,1-benzoxazin-4-one] in an inert solvent in the presence of a base,
It can be produced by reacting in the presence or absence of a dehydrating agent or a condensing agent, removing protective groups as necessary, and hydrolyzing as required.

The compound represented by the general formula (I) is

[0051]

Embedded image

(Wherein R ² , R ³ and R ¹⁰ have the same meanings as described above);

H-B ⁰ (V)

(Wherein B ⁰ has the same meaning as described above) with an amine compound represented by the formula (I) in an inert solvent or in the absence thereof. It can be manufactured by decomposition.

The compound represented by the general formula (I) is

[0056]

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(Wherein R ² , R ³ and R ¹⁰ have the same meanings as described above) and a 2-acylaminobenzoic acid derivative represented by the general formula (V) and a reactive functional derivative thereof. With an amine compound in an inert solvent in the presence of a base, in the presence or absence of a dehydrating agent or a condensing agent, removing protective groups as necessary, and hydrolyzing as required. be able to.

For example, among the compounds represented by the above general formula (I),

[0059]

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(Wherein R ¹ , R ² and R ³ have the same meaning as described above)

[0061]

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(Wherein R ² , R ³ and R ¹⁰ have the same meaning as described above) in the presence of a methanolic solution of ammonia and a catalytic amount of sodium cyanide. The reaction can be carried out by heating in a sealed tube, and the protective group can be removed if necessary.

The compounds represented by the general formulas (II) and (V) used as starting materials in the above-mentioned production method may be purchased as a commercial product, or produced by a known method described in the literature or a method similar thereto. be able to.

The compound represented by the general formula (III) used as a raw material in the production method may be purchased as a commercial product or after treating isatoic anhydride or anthranilic acid with thionyl chloride, It can be produced by reacting the amine compound represented by the formula (V) with an inert solvent in the presence of a base.

The compound represented by the general formula (IV) used as a starting material in the production method may be a known method described in the literature or a method similar thereto, or a carboxylic acid represented by the general formula (II) A derivative or a reactive functional derivative such as an acid halide or an active ester thereof, and a general formula

[0066]

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An anthranilic acid derivative represented by the formula (wherein R is a hydrogen atom or an alkyl group) is reacted with an inert solvent in the presence of a base, in the presence or absence of a dehydrating agent or a condensing agent. After the reaction, if necessary, the ester group is hydrolyzed to convert it into a carboxyl group to obtain a 2-acylaminobenzoic acid derivative represented by the above general formula (VI), followed by dehydration of acetic anhydride or the like in an inert solvent. It can be produced by ring closure in the presence of an agent or a condensing agent, or by dehydration ring closure under heating.

Among the 2-acylaminobenzamide derivatives represented by the general formula (I), compounds having an amino group, a substituted amino group, a hydroxyl group or a carboxyl group are pharmacologically acceptable by a conventional method. It can be a salt. Examples of such salts include acid addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluene. Acid addition salts with organic acids such as sulfonic acid, propionic acid, citric acid, succinic acid, tartaric acid, fumaric acid, butyric acid, oxalic acid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid, glutamic acid, aspartic acid, sodium Salts, salts with inorganic bases such as potassium salts, morpholine,
Examples thereof include salts with organic amines such as piperidine and lysine.

The compound represented by formula (I) also includes hydrates and solvates with pharmaceutically acceptable solvents such as ethanol.

The compound represented by the above general formula (I) has 2
There are two geometrical isomers. In the present invention, any of the cis-form (Z-form) compound and the trans-form (E-form) compound may be used.
Body) is preferred.

Among the compounds represented by the general formula (I), compounds having an asymmetric carbon atom have two optical isomers of R configuration and S configuration. May be used, or a mixture of these optical isomers may be used.

Among the compounds represented by the general formula (I) used in the present invention, compounds having good absorbability in oral administration include, for example, (E) -2-
(3,4-dimethoxycinnamoylamino) benzamide, (E) -2- (3,4,5-trimethoxycinnamoylamino) benzamide, (E) -N- (2-hydroxyethyl) -2- (3 , 4,5-Trimethoxycinnamoylamino) benzamide, (E) -2- (3,4-
Dimethoxycinnamoylamino) -N- (2-hydroxyethyl) benzamide, (E) -2- [2- (3,4
-Dimethoxycinnamoylamino) benzoylamino]
Benzoic acid, (E) -2- (3,4-dimethoxycinnamoylamino) -N- (2-dimethylaminoethyl) benzamide hydrochloride, (E) -N- (2-dimethylaminoethyl) -2- ( Compounds such as (3,4,5-trimethoxycinnamoylamino) benzamide hydrochloride can be mentioned.

The compound represented by the general formula (I) is a highly safe compound. For example, in an acute toxicity test using a mouse, (E) -2- (3,4-dimethoxycinnamoyl) Amino) benzamide and (E)-
2- (3,4,5-trimethoxycinnamoylamino)
No death was observed even with a single dose of benzamide of 1000 mg / kg or more.

When the pharmaceutical composition of the present invention is used for actual treatment, various dosage forms are used depending on the usage. Such dosage forms include, for example, powders, granules, fine granules,
Examples include dry syrups, tablets, capsules, ointments, injections, and eye drops.

[0075] These pharmaceutical compositions can be prepared by appropriate excipients, disintegrants,
Binders, lubricants, diluents, buffers, tonicity agents, preservatives,
It can be produced by appropriately mixing, diluting or dissolving with pharmaceutical additives such as wetting agents, emulsifiers, dispersants, stabilizers, and solubilizing agents, and dispensing according to a conventional method.

For example, a powder is prepared by adding an appropriate excipient, lubricant and the like to a 2-acylaminobenzamide derivative represented by the above general formula (I) or a salt thereof, if necessary, and mixing well. .

The tablet is represented by the general formula (I):
If necessary, appropriate excipients, disintegrants, binders, lubricants and the like are added to the acylaminobenzamide derivative or a salt thereof, and the mixture is compressed into tablets according to a conventional method. Tablets can also be used as needed
It can be coated to give film-coated tablets, sugar-coated tablets, enteric-coated sugar-coated tablets and the like.

The capsules are mixed, for example, with appropriate excipients, lubricants and the like, if necessary, and then filled into appropriate capsules to form capsules. Further, after granules or fine granules are formed by a conventional method, they may be filled.

When used as an ointment, it may be used as an eye ointment.

When used as an injection, it may be directly injected into a diseased tissue such as the cornea or vitreous body or a tissue adjacent thereto with a thin injection needle, or may be used as an intraocular perfusion solution.

The present preparation may be administered as a sustained release preparation. For example, using a sustained release polymer as a carrier,
The pellet or microcapsule is treated by incorporating the 2-acylaminobenzamide derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof into pellets or microcapsules of these sustained-release polymers. It can be surgically implanted into the tissue to be treated. Examples of the sustained-release polymer include ethylene vinyl acetate, polyhydromethacrylate, polyacrylamide, polyvinylpyrrolidone, methylcellulose, lactic acid polymer, lactic acid / glycolic acid copolymer, and the like. Preferably, a lactic acid polymer which is a biodegradable polymer And lactic acid / glycolic acid copolymer.

When the pharmaceutical composition of the present invention is used for actual treatment, administration of a 2-acylaminobenzamide derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient thereof is performed. The amount is appropriately determined depending on the weight, age, sex, degree of disease, etc. of the patient. In the case of oral administration, it can be administered in the range of about 0.1 to 1000 mg per adult per day. It can be administered in the range of approximately 0.01 to 300 mg per day.

The dose of the 2-acylaminobenzamide derivative represented by the above general formula (I) or a pharmacologically acceptable salt thereof, which is an active ingredient, depends on the type of the disease to be treated, the condition of the patient, It can be increased or decreased as appropriate depending on the difference in the therapeutic effect.

[0084]

EXAMPLES The contents of the present invention will be described in more detail with reference to the following Reference Examples, Examples and Formulation Examples, but the present invention is not limited to these contents.

Reference Example 1 Isopropyl (E) -3-isopropoxycinnamate (E) -3-Hydroxycinnamic acid (2 g) and potassium carbonate (3.7 g) suspended in N, N-dimethylformamide (20 ml) Isopropyl iodide (2.68 m
l) was added and the mixture was stirred at 80 ° C for 3 days. Water was added to the reaction solution, which was extracted with ethyl acetate. Wash the extract with saturated aqueous sodium bicarbonate,
After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent:
Methylene chloride) to give isopropyl 3-isopropoxycinnamate (1.20 g).

¹ H-NMR (CDCl ₃ , 400 MH
z) δ ppm: 1.31 (d, J = 6.3 Hz, 6
H), 1.34 (d, J = 6.1 Hz, 6H), 4.5
-4.65 (m, 1H), 5.05-5.2 (m, 1
H), 6.39 (d, J = 16.0 Hz, 1H), 6.
8-7.3 (m, 4H), 7.62 (d, J = 16.0)
Hz, 1H)

Reference Example 2 The following compound was synthesized in the same manner as in Reference Example 1. (E) Ethyl 3,5-dimethoxy-4-ethoxycinnamate

¹ H-NMR (CDCl ₃ , 400 MH
z) δ ppm: 1.25-1.5 (m, 6H);
87 (s, 6H), 4.09 (q, J = 7.1 Hz, 2
H), 4.27 (q, J = 7.1 Hz, 2H), 6.3.
5 (d, J = 15.9 Hz, 1H), 6.75 (s, 2
H), 7.61 (d, J = 15.9 Hz, 1H)

(E) -3,5-dimethoxy-4- (2-
(Hydroxyethoxy) 2-hydroxyethyl cinnamate

¹ H-NMR (CDCl ₃ , 400 MH
z) δ ppm: 3.7-4.45 (m, 14H),
6.41 (d, J = 15.9 Hz, 1H), 6.77
(S, 2H), 7.65 (d, J = 15.9 Hz, 1
H)

Reference Example 3 (E) -3-Isopropoxycinnamic acid A 2N aqueous sodium hydroxide solution (5 ml) was added to a solution of (E) -3-isopropylpropionyl cinnamate (1.1 g) in ethanol (10 ml). Was added and stirred at room temperature for 15 hours. 1N hydrochloric acid was added to the reaction solution to make the reaction solution acidic, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain (E) -3-isopropoxycinnamic acid (914 mg).

¹ H-NMR (CDCl ₃ , 400 MH
z) δ ppm: 1.36 (d, J = 6.0 Hz, 6
H), 4.5-4.65 (m, 1H), 6.43 (d,
J = 16.0 Hz, 1H), 6.9-7.4 (m, 4
H), 7.75 (d, J = 16.0 Hz, 1H)

Reference Example 4 The following compound was synthesized in the same manner as in Reference Example 3. (E) -3,5-dimethoxy-4-ethoxycinnamic acid

¹ H-NMR (CDCl ₃ , 400 MH
z) δ ppm: 1.37 (t, J = 7.1 Hz, 3
H), 3.89 (s, 6H), 4.11 (q, J = 7.
1 Hz, 2H), 6.36 (d, J = 15.9 Hz, 1
H), 6.78 (s, 2H), 7.71 (d, J = 1
5.9Hz, 1H)

(E) -3,5-dimethoxy-4- (2-
Hydroxyethoxy) cinnamic acid

¹ H-NMR (CDCl ₃ , 400 MH
z) δ ppm: 3.7-3.8 (m, 2H), 3.9
5. 1 (s, 6H), 4.1-4.25 (m, 2H),
37 (d, J = 15.9 Hz, 1H), 6.79 (s,
2H), 7.70 (d, J = 15.9 Hz, 1H)

Reference Example 5 (E) -tert-butyl 2-ethoxycarbonylcinnamate ethyl o-bromobenzoate (1.0 g), sodium iodide (720 mg) and nickel (II) bromide (190 g)
mg) was added to N, N-dimethylformamide (10 ml), and the mixture was stirred at 140 ° C for 4 hours. Tert-butyl acrylate (0.7 ml), palladium (0) bis (dibenzylideneacetone) (23 mg), tri-o
-Tolylphosphine (530 mg) and triethylamine (0.67 ml) were added, and the mixture was further stirred at 140 ° C for 3 hours. The reaction mixture was diluted with methylene chloride, the complex was filtered off, and washed with dilute aqueous acetic acid. After the solvent was distilled off under reduced pressure, the residue was dissolved in diethyl ether and washed three times with distilled water. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was separated and purified by silica gel column chromatography (elution solvent: methylene chloride).
(E) tert-Butyl-2-ethoxycarbonylcinnamate (676 mg) was obtained.

¹ H-NMR (CDCl ₃ , 400 MH
z) δ ppm: 1.41 (t, J = 7.1 Hz, 3
H), 1.54 (s, 9H), 4.40 (q, J = 7.
1 Hz, 2H), 6.23 (d, J = 15.9 Hz, 1
H), 7.35-7.65 (m, 3H), 7.94 (d
d, J = 7.8, 1.4 Hz, 1H), 8.31 (d,
J = 15.9Hz, 1H)

Reference Example 6 (E) -2-Ethoxycarbonylcinnamic acid (E) -2-tert-Butyl-2-ethoxycarbonylcinnamate (538 mg) was added to trifluoroacetic acid (5 ml) and stirred at 40 ° C. for 30 minutes. did. The solvent was distilled off under reduced pressure, a small amount of diethyl ether was added to the residue, and the mixture was treated with ultrasonic waves. Then, (E) -2-ethoxycarbonylcinnamic acid (33
9 mg).

¹ H-NMR (DMSO-d ₆ , 400
MHz) δ ppm: 1.34 (t, J = 7.1 Hz,
5H, 4.34 (q, J = 7.1 Hz, 2H), 6.
43 (d, J = 15.9 Hz, 1H), 7.45-7.
95 (m, 4H), 8.23 (d, J = 15.9 Hz,
1H), 12.4-12.65 (br, 1H)

Reference Example 7 (E) -3,4-Ethylenedioxycinnamic acid 3,4-ethylenedioxybenzaldehyde (2.0
g) and malonic acid (1.5 g) in pyridine (20 m
l) Piperidine (24 μl) was added to the solution, and the mixture was heated under reflux for 20 hours. Further, malonic acid (7.5 g) was added, and the mixture was heated under reflux for 20 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in a 2N aqueous sodium hydroxide solution. After washing the aqueous solution with methylene chloride, concentrated hydrochloric acid was added to make the solution acidic. The precipitate was collected by filtration and washed with water and hexane to obtain (E) -3,4-ethylenedioxycinnamic acid (1.48 g).

¹ H-NMR (DMSO-d ₆ , 400
MHz) δ ppm: 4.2-4.4 (m, 4H),
6.37 (d, J = 16.0 Hz, 1H), 6.89
(D, J = 8.4 Hz, 1H), 7.18 (dd, J =
8.4, 2.0 Hz, 1H), 7.24 (d, J = 2.
0 Hz, 1H), 7.48 (d, J = 16.0 Hz, 1
H), 12.0-12.6 (br, 1H)

Reference Example 8 (E) -2- (2-Carboxycinnamoylamino) benzoic acid (E) -2- (2-Ethoxycarbonylcinnamoylamino) benzamide (510.8 mg) in acetic acid (2m
l) Concentrated hydrochloric acid (2 ml) was added to the solution, and the mixture was stirred at 100 ° C for 5 minutes. The solvent was distilled off under reduced pressure, and ethanol (2
ml) and 1 N aqueous sodium hydroxide solution (2 ml)
Was added and stirred at 100 ° C. for 4 hours. The reaction solution was acidified with 1N hydrochloric acid, and the precipitate was collected by filtration and washed with diethyl ether to obtain (E) -2- (2-carboxycinnamoylamino) benzoic acid (144 mg).

¹ H-NMR (DMSO-d ₆ , 400 M
Hz) δ ppm: 6.76 (d, J = 15.6 Hz,
1H), 7.1-8.05 (m, 7H), 8.34.
(D, J = 15.6 Hz, 1H), 8.59 (d, J =
7.5 Hz, 1H), 11.40 (brs, 1H), 1
3.0-14.0 (br, 2H)

Reference Example 9 (E) -4-Acetoxy-3,5-dimethoxycinnamic acid To a solution of (E) -3,5-dimethoxy-4-hydroxycinnamic acid (365 mg) in acetic anhydride (5 ml) was added water. Sodium oxide (65 mg) was added, and the mixture was stirred at 100 ° C for 20 minutes. The reaction solution was concentrated under reduced pressure, 2N hydrochloric acid was added to the residue to make it acidic, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain (E) -4-acetoxy-3,5-dimethoxycinnamic acid (334 mg).

¹ H-NMR (DMSO-d ₆ , 400 M
Hz) δ ppm: 2.26 (s, 3H), 3.81
(S, 6H), 6.64 (d, J = 16.0 Hz, 1
H), 7.12 (s, 2H), 7.57 (d, J = 1
6.0 Hz, 1H), 12.3-12.5 (br, 1
H)

Reference Example 10 (E) -4- (2-acetoxyethoxy) -3,5-dimethoxycinnamic acid (E) -3,5-dimethoxy-4- (2-hydroxyethoxy) cinnamic acid (292 mg) ) Of pyridine (6 ml)
Acetic anhydride (0.31 ml) was added to the solution, and the mixture was stirred at room temperature for 13 hours. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (elution solvent: methylene chloride / diethyl ether = 1/1) to give (E) -4- (2-acetoxy). Ethoxy) -3,5-dimethoxycinnamic acid (60
mg).

¹ H-NMR (CDCl ₃ , 400 MH
z) δ ppm: 2.09 (s, 3H), 3.88
(S, 6H), 4.2-4.4 (m, 4H), 6.36
(D, J = 15.9 Hz, 1H), 6.78 (s, 2
H), 7.70 (d, J = 15.9 Hz, 1H)

Reference Example 11 2-Amino-N- (3-phenylpropyl) benzamide A solution of isatoic anhydride (500 mg) in N, N-dimethylformamide (3 ml) was treated with 4-dimethylaminopyridine (37 mg) and 3-phenylpropylamine. (43
6 mg) and stirred at room temperature for 1 day. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 2-amino-N- (3-phenylpropyl) benzamide (760 mg).

¹ H-NMR (CDCl ₃ , 400 MH
z) δ ppm: 1.9-2.0 (m, 2H), 2.6
5-2.8 (m, 2H), 3.4-3.55 (m, 2
H), 5.48 (brs, 2H), 5.98 (brs,
1H), 6.55-6.95 (m, 2H), 7.1-
7.4 (m, 7H)

Reference Example 12 2-Amino-N- [2- (2-hydroxyethoxy) ethyl] benzamide In ethanol (5 ml), isatoic anhydride (1.0 g) and 2- (2-aminoethoxy) ethanol (645 mg) were added.
Was added and heated under reflux for 10 minutes. After evaporating the solvent under reduced pressure, the residue was separated and purified by silica gel column chromatography (eluent: chloroform / methanol = 10/1) to give 2-amino-N- [2- (2-hydroxyethoxy) ethyl] benzamide ( 1.32 g).

¹ H-NMR (CDCl ₃ , 400 MH
z) δ ppm: 2.05-2.45 (br, 1H),
3.55-3.85 (m, 8H), 5.25-5.75
(Br, 2H), 6.50-6.75 (m, 3H),
7.15-7.25 (m, 1H), 7.35 (dd, J
= 7.9, 1.5Hz, 1H)

Reference Example 13 The following compound was synthesized in the same manner as in Reference Example 12. 2-amino-N- (2-hydroxyethyl) benzamide

¹ H-NMR (CDCl ₃ , 400 MH
z) δ ppm: 2.66 (t, J = 5.1 Hz, 1
H), 3.50-3.65 (m, 2H), 3.75-
3.9 (m, 2H), 5.50 (brs, 2H), 6.
40-6.75 (m, 3H), 7.15-7.30
(M, 1H), 7.34 (dd, J = 7.9, 1.5H
z, 1H)

2-amino-N- (4-hydroxybutyl) benzamide

¹ H-NMR (CDCl ₃ , 400 MH
z) δ ppm: 1.40-2.00 (m, 4H),
3.40-3.50 (m, 2H), 3.72 (t, J =
6.0 Hz, 2H), 5.30-5.70 (br, 2
H), 6.34 (brs, 1H), 6.55-6.75.
(M, 2H), 7.10-7.40 (m, 2H)

2-amino-N- (2-dimethylaminoethyl) benzamide

¹ H-NMR (CDCl ₃ , 400 MH
z) δ ppm: 2.26 (s, 6H), 2.50
(T, J = 6.0 Hz, 2H), 3.40-3.55
(M, 2H), 5.54 (brs, 2H), 6.60-
6.80 (m, 3H), 7.15-7.25 (m, 1
H), 7.35 (dd, J = 7.8, 1.4 Hz, 1
H)

2-Amino-N- [2- [bis (2-hydroxyethyl) amino] ethyl] benzamide

¹ H-NMR (CDCl ₃ , 400 MH
z) δ ppm: 2.61 (t, J = 5.0 Hz, 4
H), 2.69 (t, J = 5.5 Hz, 2H), 3.4
-3.5 (m, 2H), 3.57 (t, J = 5.0H)
z, 4H), 5.41 (brs, 2H), 6.6-7.
35 (m, 4H), 7.40 (dd, J = 7.8, 1.
3Hz, 1H)

Reference Example 14 (E) -2- (4-Dimethylaminocinnamoylamino) benzoic acid N-carboxymethylcarbonylanthranilic acid (5
g) and 4-dimethylaminobenzaldehyde (3.
To a solution of 43 g) in toluene (50 ml) was added piperidine (2.22 ml), and the mixture was heated under reflux with a Dean-Stark trap for 18 hours. The toluene was distilled off under reduced pressure, and the residue was separated and purified by silica gel column chromatography (elution solvent: ethyl acetate). The obtained crystals were washed with diethyl ether, and then (E) -2- (4-dimethylaminocinnamoyl). ) Aminobenzoic acid (1.14 g)
I got

¹ H-NMR (DMSO-d ₆ , 400 M
Hz) δ ppm: 2.98 (s, 6H), 6.54
(D, J = 15.5 Hz, 1H), 6.73 (d, J =
8.9 Hz, 2H), 7.1-7.7 (m, 5H),
8.00 (dd, J = 7.9, 1.6 Hz, 1H),
8.63 (d, J = 8.4 Hz, 1H), 11.25
(S, 1H), 13.3-13.9 (br, 1H)

Reference Example 15 (E) -2- (4-Dimethylaminostyryl) -3,1
-Benzoxazin-4-one (E) -2- (4-Dimethylaminocinnamoylamino) benzoic acid (500 mg) was dissolved in acetic anhydride (10 ml) and stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure,
(E) -2- (4-dimethylaminostyryl) -3,1
-Benzoxazin-4-one (480 mg) was obtained.

¹ H-NMR (CDCl ₃ , 400 MH
z) δ ppm: 3.04 (s, 6H), 6.56
(D, J = 15.9 Hz, 1H), 6.65-7.85
(M, 8H), 8.19 (dd, J = 7.9, 1.4H
z, 1H)

Reference Example 16 (E) -2- (2-Carboxystyryl) -3,1-benzoxazin-4-one (E) -2- (2-carboxycinnamoylamino) benzoic acid (70 mg) was added to pyridine. (1 ml), acetic anhydride (42.5 μl) was added, and the mixture was stirred at room temperature for 3 days.
The reaction solution was acidified with 1N hydrochloric acid, and the precipitate was collected by filtration.
After washing with 1N hydrochloric acid and water, (E) -2- (2-carboxystyryl) -3,1-benzoxazin-4-one (32.6 mg) was obtained.

¹ H-NMR (DMSO-d ₆ , 400 M
Hz) δ ppm: 6.92 (d, J = 16.1 Hz,
1H), 7.5-8.2 (m, 8H), 8.53 (d,
J = 16.1 Hz, 1H), 13.33 (brs, 1
H)

Reference Example 17 2- (2-Aminobenzoylamino) benzoic acid Anthranilic acid (2.00 g) and isatoic anhydride (2.38 g) were added to a 1 N aqueous solution of sodium hydroxide (2.
1.9 ml) and water (10 ml).
For 1 hour. After adding acetic acid (2.5 ml) to the reaction solution, the precipitated solid was collected by filtration and recrystallized from methanol to obtain 2- (2-aminobenzoylamino) benzoic acid (1.49 g).

¹ H-NMR (DMSO-d ₆ , 400 M
Hz) δ ppm: 6.5-7.0 (m, 2H), 7.
1-7.8 (m, 4H), 8.04 (dd, J = 7.
9, 1.6 Hz, 1 H), 8.65 (d, J = 8.4 H)
z, 1H), 11.93 (s, 1H)

Reference Example 18 2- (2-aminophenyl) -3,1-benzoxazin-4-one 2- (2-aminobenzoylamino) benzoic acid (1.4
9g) was stirred in concentrated sulfuric acid (15ml) at room temperature for 30 minutes. The reaction solution was poured into water, and the precipitated solid was collected by filtration, washed successively with a saturated aqueous solution of sodium hydrogen carbonate and water, and then washed with 2- (2
-Aminophenyl) -3,1-benzoxazine-4-
On (884 mg) was obtained.

¹ H-NMR (DMSO-d ₆ , 400 M
Hz) δ ppm: 6.55-6.7 (m, 1H),
6.87 (d, J = 8.4 Hz, 1H), 7.2-7.
65 (m, 4H), 7.7-8.0 (m, 3H), 8.
12 (dd, J = 7.8, 1.4 Hz, 1H)

Example 1 (E) -2- (3-ethoxycinnamoylamino) benzamide (Compound 1) Thionyl chloride was added to a suspension of (E) -3-ethoxycinnamic acid (448 mg) in toluene (2.5 ml). (826mg)
And a catalytic amount of N, N-dimethylformamide, and the mixture was stirred at 80 ° C. for 3 hours. The reaction solution was concentrated under reduced pressure, and 2-aminobenzamide (314 m
g) and pyridine (8 ml) were added, and the mixture was heated under reflux at 130 ° C. for 3 hours. After the reaction solution was poured into water and stirred, the precipitate was collected by filtration. The obtained precipitate was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate, water and diethyl ether to give (E) -2.
-(3-ethoxycinnamoylamino) benzamide (458 mg) was obtained.

¹ H-NMR (CDCl ₃ , 400 MH
z) δ ppm: 1.4-1.5 (m, 3H), 4.0
8 (q, J = 7.0 Hz, 2H), 6.48 (brs,
1H), 6.59 (d, J = 15.5 Hz, 1H),
6.8-7.8 (m, 9H), 8.76 (d, J = 8.
4Hz, 1H), 11.86 (brs, 1H)

Example 2 (E) -2- (3-Isopropoxycinnamoylamino) benzamide (compound 2) A suspension of (E) -3-isopropoxycinnamic acid (500 mg) in toluene (5 ml) was chlorided. Thionyl (3 ml) and one drop of N, N-dimethylformamide were added,
For 30 minutes. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 ml).
Aminobenzamide (693 mg) was added, and the mixture was stirred at room temperature for 5 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
(E) -2- (3-Isopropoxycinnamoylamino) benzamide (738 mg) was obtained.

¹ H-NMR (DMSO-d ₆ , 400M
Hz) δ ppm: 1.28 (d, J = 6.0 Hz, 6
H), 4.65-4.8 (m, 1H), 6.83 (d,
J = 15.6 Hz, 1H), 6.9-7.9 (m, 9
H), 8.30 (brs, 1H), 8.57 (dd, J
= 8.4, 1.0 Hz, 1H), 11.85 (s, 1
H)

Example 3 (E) -2- (2-ethoxycarbonylcinnamoylamino) benzamide (compound 3) (E) -2-ethoxycarbonylcinnamic acid (295 m
g) in toluene (2 ml) was added to thionyl chloride (195).
μl) and 1 drop of N, N-dimethylformamide were added, and the mixture was stirred at 50 ° C. for 1 hour. After distilling off the solvent under reduced pressure,
The residue was dissolved in tetrahydrofuran (1 ml) and added dropwise to a solution of 2-aminobenzamide (456 mg) in tetrahydrofuran (1 ml) under ice cooling. After stirring at room temperature for 5 minutes, the precipitated salt was filtered off and the solvent was distilled off under reduced pressure.
The residue was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution, distilled water and diethyl ether to give (E) -2
-(2-Ethoxycarbonylcinnamoylamino) benzamide (418 mg) was obtained.

¹ H-NMR (CDCl ₃ , 400 MH
z) δ ppm: 1.41 (t, J = 7.1 Hz, 3
H), 4.42 (q, J = 7.1 Hz, 2H), 5.3
−6.4 (br, 2H), 6.46 (d, J = 15.6)
Hz, 1H), 7.0-7.7 (m, 6H), 7.95
(Dd, J = 7.9, 1.2 Hz, 1H), 8.44
(D, J = 15.6 Hz, 1H), 8.82 (dd, J
= 8.7, 1.1 Hz, 1H), 11.52 (s, 1
H)

Example 4 The following compounds were synthesized in the same manner as in Examples 1 to 3. (E) -2- (3,4-dimethoxycinnamoylamino) benzamide (compound 4)

¹ H-NMR (DMSO-d ₆ , 400 M
Hz) δ ppm: 3.80 (s, 3H), 3.84
(S, 3H), 6.71 (d, J = 15.7 Hz, 1
H), 6.95-7.9 (m, 8H), 8.28 (br
s, 1H), 8.59 (dd, J = 8.4, 0.9H)
z, 1H), 11.80 (s, 1H)

(E) -2- (2,3-Dimethoxycinnamoylamino) benzamide (compound 5)

¹ H-NMR (DMSO-d ₆ , 400 M
Hz) δ ppm: 3.78 (s, 3H), 3.83
(S, 3H), 6.77 (d, J = 15.9 Hz, 1
H), 7.0-7.9 (m, 8H), 8.31 (br
s, 1H), 8.57 (dd, J = 8.4, 1.0H)
z, 1H), 11.98 (s, 1H)

(E) -2- (3-benzyloxycinnamoylamino) benzamide (compound 6)

¹ H-NMR (DMSO-d ₆ , 400 M
Hz) δ ppm: 5.17 (s, 2H), 6.85
(D, J = 15.6 Hz, 1H), 7.0-7.9.
(M, 14H), 8.31 (brs, 1H), 8.5-
8.65 (m, 1H), 11.88 (s, 1H)

(E) -2- (3-Butoxycinnamoylamino) benzamide (Compound 7)

¹ H-NMR (DMSO-d ₆ , 400M
Hz) δ ppm: 0.95 (t, J = 7.4 Hz, 3
H), 1.4-1.8 (m, 4H), 4.03 (t, J
= 6.5 Hz, 2H), 6.85 (d, J = 15.7H)
z, 1H), 6.9-7.9 (m, 9H), 8.30
(Brs, 1H), 8.57 (dd, J = 8.3, 0.
9Hz, 1H), 11.85 (s, 1H)

(E) -2- (4-methoxycinnamoylamino) benzamide (compound 8)

¹ H-NMR (DMSO-d ₆ , 400 M
Hz) δ ppm: 3.80 (s, 3H), 6.64
(D, J = 15.6 Hz, 1H), 6.9-7.9.
(M, 9H), 8.27 (brs, 1H), 8.57
(Dd, J = 8.3, 0.9 Hz, 1H), 11.84
(S, 1H)

(E) -2- (4-ethoxycinnamoylamino) benzamide (compound 9)

¹ H-NMR (DMSO-d ₆ , 400M
Hz) δ ppm: 1.34 (t, J = 6.9 Hz, 3
H), 4.08 (q, J = 6.9 Hz, 2H), 6.6.
3 (d, J = 15.6 Hz, 1H), 6.9-7.85
(M, 9H), 8.27 (brs, 1H), 8.5-
8.7 (m, 1H), 11.84 (s, 1H)

(E) -2- (3-Cyclohexylmethoxycinnamoylamino) benzamide (compound 10)

¹ H-NMR (DMSO-d ₆ , 400M
Hz) δ ppm: 0.8-2.0 (m, 11H),
3.84 (d, J = 6.1 Hz, 2H), 6.5-8.
1 (m, 10H), 8.32 (brs, 1H), 8.5
7 (d, J = 8.2 Hz, 1H), 11.85 (s, 1
H)

(E) -2- (3-methoxycinnamoylamino) benzamide (compound 11)

¹ H-NMR (DMSO-d ₆ , 400M
Hz) δ ppm: 3.81 (s, 3H), 6.84
(D, J = 15.7 Hz, 1H), 6.9-7.9
(M, 9H), 8.30 (brs, 1H), 8.57
(D, J = 8.2 Hz, 1H), 11.87 (s, 1
H)

(E) -2- (2,4-Dimethoxycinnamoylamino) benzamide (Compound 12)

¹ H-NMR (CDCl ₃ , 400 MH
z) δ ppm: 3.84 (s, 3H), 3.88
(S, 3H), 5.2-6.2 (br, 2H), 6.4
6 (d, J = 2.4 Hz, 1H), 6.51 (dd, J
= 8.4, 2.3 Hz, 1H), 6.61 (d, J = 1
5.6Hz, 1H), 7.0-7.6 (m, 4H),
7.95 (d, J = 15.7 Hz, 1H), 8.8-
8.9 (m, 1H), 11.29 (brs, 1H)

(E) -2- (2,5-dimethoxycinnamoylamino) benzamide (compound 13)

¹ H-NMR (DMSO-d ₆ , 400M
Hz) δ ppm: 3.77 (s, 3H), 3.82
(S, 3H), 6.82 (d, J = 15.7 Hz, 1
H), 6.9-8.6 (m, 10H), 11.86.
(S, 1H)

(E) -2- (3-Nitrocinnamoylamino) benzamide (compound 14)

¹ H-NMR (DMSO-d ₆ , 400M
Hz) δ ppm: 7.0-8.7 (m, 12H), 1
1.89 (s, 1H)

(E) -2- (4-methylcinnamoylamino) benzamide (compound 15)

¹ H-NMR (DMSO-d ₆ , 400M
Hz) δ ppm: 2.33 (s, 3H), 6.73
(D, J = 15.6 Hz, 1H), 7.1-7.9
(M, 9H), 8.29 (brs, 1H), 8.57
(Dd, J = 8.3, 0.9 Hz, 1H), 11.89
(S, 1H)

(E) -2- (3-ethoxy-4-methoxycinnamoylamino) benzamide (compound 16)

¹ H-NMR (DMSO-d ₆ , 400M
Hz) δ ppm: 1.35 (t, J = 6.9 Hz, 3
H), 3.79 (s, 3H), 4.09 (q, J = 6.
9 Hz, 2H), 6.70 (d, J = 15.5 Hz, 1
H), 6.9-7.9 (m, 8H), 8.29 (br
s, 1H), 8.58 (dd, J = 8.4, 1.0H)
z, 1H), 11.78 (s, 1H)

(E) -2- (4-ethoxy-3-methoxycinnamoylamino) benzamide (compound 17)

¹ H-NMR (DMSO-d ₆ , 400M
Hz) δ ppm: 1.33 (t, J = 6.9 Hz, 3
H), 3.83 (s, 3H), 4.05 (q, J = 6.
9 Hz, 2H), 6.71 (d, J = 15.5 Hz, 1
H), 6.9-8.4 (m, 9H), 8.59 (dd,
J = 8.4, 1.0 Hz, 1H), 11.80 (s, 1
H)

(E) -2- (4-cyanocinnamoylamino) benzamide (compound 18)

¹ H-NMR (DMSO-d ₆ , 400M
Hz) δ ppm: 7.03 (d, J = 15.6 Hz,
1H), 7.1-8.4 (m, 10H), 8.57 (d
d, J = 8.3, 0.9 Hz, 1H), 11.95
(S, 1H)

(E) -N-butyl-2- (3,4-dimethoxycinnamoylamino) benzamide (compound 1
9)

¹ H-NMR (CDCl ₃ , 400 MH
z) δ ppm: 0.98 (t, J = 7.3 Hz, 3
H), 1.3-1.8 (m, 4H), 3.46 (td,
J = 7.1, 5.7 Hz, 2H), 3.92 (s, 3
H), 3.96 (s, 3H), 6.28 (brs, 1
H), 6.48 (d, J = 15.5 Hz, 1H), 6.
87 (d, J = 8.2 Hz, 1H), 7.0-7.6
(M, 5H), 7.68 (d, J = 15.6 Hz, 1
H), 8.75 (dd, J = 8.4, 0.9 Hz, 1
H), 11.30 (s, 1H)

(E) -2- (3,4-Dimethoxycinnamoylamino) -N- (3-phenylpropyl) benzamide (Compound 20)

¹ H-NMR (CDCl ₃ , 400 MH
z) δ ppm: 1.95-2.05 (m, 2H),
2.76 (t, J = 7.4 Hz, 2H), 3.45 −
3.55 (m, 2H), 3.92 (s, 3H), 3.9
5 (s, 3H), 6.28 (brs, 1H), 6.47
(D, J = 15.5 Hz, 1H), 6.8-7.55
(M, 11H), 7.67 (d, J = 15.5 Hz, 1
H), 8.65-8.8 (m, 1H), 11.29
(S, 1H)

(E) -2- (2-ethoxycinnamoylamino) benzamide (compound 21)

¹ H-NMR (CDCl ₃ , 400 MH
z) δ ppm: 1.50 (t, J = 6.9 Hz, 3
H), 4.12 (q, J = 6.9 Hz, 2H), 6.2
6 (brs, 1H), 6.73 (d, J = 15.7H
z, 1H), 6.8-7.8 (m, 8H), 8.03.
(D, J = 15.7 Hz, 1H), 8.79 (dd, J
= 8.4, 0.8 Hz, 1H), 11.71 (s, 1
H)

(E) -2- (3-chlorocinnamoylamino) benzamide (compound 22)

¹ H-NMR (DMSO-d ₆ , 400M
Hz) δ ppm: 6.95 (d, J = 15.6 Hz,
1H), 7.0-8.6 (m, 11H), 11.88.
(S, 1H)

(E) -2- (3-Fluorosinnamoylamino) benzamide (Compound 23)

¹ H-NMR (DMSO-d ₆ , 400M
Hz) δ ppm: 6.93 (d, J = 15.6 Hz,
1H), 7.1-7.95 (m, 9H), 8.32 (b
rs, 1H), 8.58 (dd, J = 8.3, 0.9H
z, 1H), 11.91 (s, 1H)

(E) -2- (2-methoxycinnamoylamino) benzamide (compound 24)

¹ H-NMR (DMSO-d ₆ , 400M
Hz) δ ppm: 3.88 (s, 3H), 6.76
(D, J = 15.7 Hz, 1H), 6.9-7.9
(M, 9H), 8.30 (brs, 1H), 8.58
(Dd, J = 8.3, 0.9 Hz, 1H), 11.92
(S, 1H)

(E) -2- (2,4,5-trimethoxycinnamoylamino) benzamide (compound 25)

¹ H-NMR (DMSO-d ₆ , 400M
Hz) δ ppm: 3.77 (s, 3H), 3.84
(S, 3H), 3.87 (s, 3H), 6.68 (d,
J = 15.6 Hz, 1H), 6.72 (s, 1H),
7.0-7.9 (m, 6H), 8.28 (brs, 1
H), 8.58 (d, J = 8.3 Hz, 1H), 11.
75 (s, 1H)

(E) -2- (3,4,5-trimethoxycinnamoylamino) benzamide (compound 26)

¹ H-NMR (DMSO-d ₆ , 400M
Hz) δ ppm: 3.69 (s, 3H), 3.84
(S, 6H), 6.83 (d, J = 15.5 Hz, 1
H), 7.07 (s, 2H), 7.1-8.7 (m, 7
H), 11.80 (s, 1H)

(E) -2-cinnamoylaminobenzamide (compound 27)

¹ H-NMR (DMSO-d ₆ , 400M
Hz) δ ppm: 6.80 (d, J = 15.7 Hz,
1H), 7.1-7.9 (m, 10H), 8.28 (b
rs, 1H), 8.57 (dd, J = 8.4, 0.9H)
z, 1H), 11.91 (s, 1H)

(E) -2- (4-chlorocinnamoylamino) benzamide (compound 28)

¹ H-NMR (DMSO-d ₆ , 400M
Hz) δ ppm: 6.85 (d, J = 15.6 Hz,
1H), 7.0-7.9 (m, 9H), 8.28 (br
s, 1H), 8.57 (d, J = 7.8 Hz, 1H),
11.90 (s, 1H)

(E) -2- (4-hydroxy-3-methoxycinnamoylamino) benzamide (compound 29)

¹ H-NMR (CDCl ₃ , 400 MH
z) δ ppm: 3.98 (s, 3H), 6.09 (b
rs, 1H), 6.58 (d, J = 15.8 Hz, 1
H), 6.9-8.2 (m, 8H)

(E) -2- (3,4-Methylenedioxycinnamoylamino) benzamide (Compound 30)

¹ H-NMR (DMSO-d ₆ , 400M
Hz) δ ppm: 6.20 (s, 2H), 6.80
(D, J = 15.5 Hz, 1H), 7.07 (d, J =
8.0 Hz, 1H), 7.2-8.0 (m, 7H),
8.39 (brs, 1H), 8.70 (dd, J = 8.
4,1.0 Hz, 1H), 11.94 (s, 1H)

(E) -2- (2,3,4-trimethoxycinnamoylamino) benzamide (compound 31)

¹ H-NMR (DMSO-d ₆ , 400M
Hz) δ ppm: 3.77 (s, 3H), 3.84
(S, 3H), 3.85 (s, 3H), 6.68 (d,
J = 15.8 Hz, 1H), 6.89 (d, J = 8.8)
Hz, 1H), 7.05-8.4 (m, 7H), 8.5.
9 (d, J = 8.3 Hz, 1H), 11.93 (s, 1
H)

(E) -2- (3,5-Dimethoxycinnamoylamino) benzamide (Compound 32)

¹ H-NMR (DMSO-d ₆ , 400M
Hz) δ ppm: 3.80 (s, 6H), 6.45 −
7.9 (m, 9H), 8.30 (brs, 1H), 8.
57 (d, J = 7.6 Hz, 1H), 11.83 (s,
1H)

(E) -2- (4-acetylcinnamoylamino) benzamide (compound 33)

¹ H-NMR (DMSO-d ₆ , 400M
Hz) δ ppm: 2.60 (s, 3H), 6.96
(D, J = 15.7 Hz, 1H), 7.1-7.85
(M, 5H), 7.87 (d, J = 8.4 Hz, 2
H), 7.98 (d, J = 8.4 Hz, 2H), 8.2.
8 (brs, 1H), 8.57 (dd, J = 8.4,
1.0 Hz, 1H), 11.94 (s, 1H)

(E) -2- (4-methylsulfonylcinnamoylamino) benzamide (compound 34)

¹ H-NMR (DMSO-d ₆ , 400M
Hz) δ ppm: 3.24 (s, 3H), 7.01
(D, J = 15.7 Hz, 1H), 7.1-7.85
(M, 5H), 7.95 (d, J = 8.6 Hz, 2
H), 7.99 (d, J = 8.6 Hz, 2H), 8.2
8 (brs, 1H), 8.56 (dd, J = 8.4,
1.0 Hz, 1H), 11.94 (s, 1H)

(E) -2- (3,5-Dimethoxy-4-
Ethoxycinnamoylamino) benzamide (compound 3
5)

¹ H-NMR (CDCl ₃ , 400 MH
z) δ ppm: 1.37 (t, J = 7.1 Hz, 3
H), 3.90 (s, 6H), 4.10 (q, J = 7.
1Hz, 2H), 5.45-6.45 (br, 2H),
6.51 (d, J = 15.5 Hz, 1H), 6.80
(S, 2H), 7.05-7.6 (m, 3H), 7.6
5 (d, J = 15.5 Hz, 1H), 8.82 (dd,
J = 8.8, 1.1 Hz, 1H), 11.44 (s, 1
H)

(E) -2- (2,4,6-trimethoxycinnamoylamino) benzamide (Compound 36)

¹ H-NMR (DMSO-d ₆ , 400M
Hz) δ ppm: 3.84 (s, 3H), 3.88
(S, 6H), 6.31 (s, 2H), 6.78 (d,
J = 15.8 Hz, 1H), 7.05-7.85 (m,
4H), 7.91 (d, J = 15.8 Hz, 1H),
8.27 (brs, 1H), 8.60 (dd, J = 8.
4,1.0 Hz, 1H), 11.86 (s, 1H)

(E) -2- (3,4-Ethylenedioxycinnamoylamino) benzamide (Compound 37)

¹ H-NMR (DMSO-d ₆ , 400 M
Hz) δ ppm: 4.2-4.4 (m, 4H), 6.
65 (d, J = 15.6 Hz, 1H), 6.89 (d,
J = 8.4 Hz, 1H), 7.1-7.9 (m, 7
H), 8.29 (brs, 1H), 8.57 (d, J =
8.4 Hz, 1H), 11.81 (s, 1H)

Example 5 (E) -2- (3,4-Dimethoxycinnamoylamino) -N- (2-dimethylaminoethyl) benzamide (Compound 38) 2-amino-N- (2-dimethylaminoethyl) Benzamide (500 mg) was added to tetrahydrofuran (10 m
1), triethylamine (370 μl) and then (E) -3,4-dimethoxycinnamic acid chloride (600
mg) and stirred at room temperature for 15 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by aminopropylated silica gel column chromatography (elution solvent: ethyl acetate), and (E) -2- (3,4-dimethoxycinnamoylamino) -N- (2-dimethylaminoethyl) benzamide (416 mg) ) Got.

¹ H-NMR (CDCl ₃ , 400 MH
z) δ ppm: 2.28 (s, 6H), 2.55
(T, J = 5.9 Hz, 2H), 3.45-3.55
(M, 2H), 3.92 (s, 3H), 3.96 (s,
3H), 6.49 (d, J = 15.5 Hz, 1H),
6.87 (d, J = 8.3 Hz, 1H), 7.00-
7.20 (m, 4H), 7.45-7.55 (m, 2
H), 7.69 (d, J = 15.5 Hz, 1H), 8.
78 (d, J = 8.0 Hz, 1H), 11.48 (s,
1H)

Example 6 The following compounds were synthesized in the same manner as in Example 5. (E) -N- (2-dimethylaminoethyl) -2- (4
-Ethoxy-3-methoxycinnamoylamino) benzamide (compound 39)

¹ H-NMR (CDCl ₃ , 400 MH
z) δ ppm: 1.49 (t, J = 7.0 Hz, 3
H), 2.29 (s, 6H), 2.55 (t, J = 5.
9Hz, 2H), 3.45-3.6 (m, 2H), 3.
95 (s, 3H), 4.15 (q, J = 7.0 Hz, 2
H), 6.49 (d, J = 15.5 Hz, 1H), 6.
87 (d, J = 8.4 Hz, 1H), 6.95-7.6
(M, 6H), 7.68 (d, J = 15.5 Hz, 1
H), 8.79 (d, J = 8.7 Hz, 1H), 11.
47 (s, 1H)

(E) -N- (2-dimethylaminoethyl) -2- (3,4,5-trimethoxycinnamoylamino) benzamide (Compound 40)

¹ H-NMR (CDCl ₃ , 400 MH
z) δ ppm: 2.29 (s, 6H), 2.56
(T, J=5.9@z, 2H), 3.45-3.60
(M, 2H), 3.88 (s, 3H), 3.92 (s,
6H), 6.53 (d, J = 15.5 Hz, 1H),
6.80 (s, 2H), 7.05-7.6 (m, 4
H), 7.65 (d, J = 15.5 Hz, 1H), 8.
78 (d, J = 8.3 Hz, 1H), 11.51 (s,
1H)

(E) -2- (3,4-Dimethoxycinnamoylamino) -N- [2- (2-hydroxyethoxy) ethyl] benzamide (Compound 41)

¹ H-NMR (CDCl ₃ , 400 MH
z) δ ppm: 3.05-3.15 (m, 1H),
3.60-3.85 (m, 8H), 3.93 (s, 3
H), 3.97 (s, 3H), 6.43 (d, J = 1
5.5 Hz, 1 H), 6.88 (d, J = 8.3 Hz,
1H), 6.95-7.05 (m, 1H), 7.12.
(D, J = 1.8 Hz, 1H), 7.17 (dd, J =
8.3, 1.8 Hz, 1H), 7.35-7.50
(M, 3H), 7.69 (d, J = 15.5 Hz, 1
H), 8.56 (d, J = 8.3 Hz, 1H), 11.
15 (s, 1H)

(E) -N- [2- (2-hydroxyethoxy) ethyl] -2- (3,4,5-trimethoxycinnamoylamino) benzamide (compound 42)

¹ H-NMR (CDCl ₃ , 400 MH
z) δ ppm: 2.90-3.00 (m, 1H),
3.60-3.85 (m, 8H), 3.89 (s, 3
H), 3.93 (s, 6H), 6.48 (d, J = 1
5.5 Hz, 1H), 6.82 (s, 2H), 6.95
−7.05 (m, 1H), 7.25-7.55 (m, 3
H), 7.66 (d, J = 15.5 Hz, 1H), 8.
55-8.65 (m, 1H), 11.21 (s, 1H)

(E) -2- (4-ethoxy-3-methoxycinnamoylamino) -N- [2- (2-hydroxyethoxy) ethyl] benzamide (compound 43)

¹ H-NMR (CDCl ₃ , 400 MH
z) δ ppm: 1.49 (t, J = 7.0 Hz, 3
H), 2.85-3.00 (br, 1H), 3.60-
3.85 (m, 8H), 3.95 (s, 3H), 4.1
5 (q, J = 7.0 Hz, 2H), 6.43 (d, J =
15.5 Hz, 1 H), 6.87 (d, J = 8.2 H)
z, 1H), 6.95-7.5 (m, 6H), 7.68
(D, J = 15.5 Hz, 1H), 8.59 (d, J =
8.3 Hz, 1H), 11.16 (s, 1H)

(E) -N- (2-hydroxyethyl)-
2- (3,4,5-trimethoxycinnamoylamino)
Benzamide (Compound 44)

¹ H-NMR (CDCl ₃ , 400 MH
z) δ ppm: 2.37 (t, J = 5.0 Hz, 1
H), 3.55-3.70 (m, 2H), 3.80-
4.00 (m, 11H), 6.50 (d, J = 15.5)
Hz, 1H), 6.80 (s, 2H), 6.85-6.
95 (m, 1H), 7.00-7.15 (m, 1H)
7.45-7.55 (m, 2H), 7.65 (d, J =
15.5 Hz, 1H), 8.65-8.75 (m, 1
H), 11.26 (s, 1H)

(E) -2- (3,4-Dimethoxycinnamoylamino) -N- (2-hydroxyethyl) benzamide (Compound 45)

¹ H-NMR (CDCl ₃ , 400 MH
z) δ ppm: 2.40-2.65 (br, 1H),
3.60-3.95 (m, 7H), 3.96 (s, 3
H), 6.45 (d, J = 15.5 Hz, 1H), 6.
80-7.20 (m, 5H), 7.40-7.55
(M, 2H), 7.68 (d, J = 15.5 Hz, 1
H), 8.6-8.75 (m, 1H), 11.20.
(S, 1H)

(E) -2- (3,4-Dimethoxycinnamoylamino) -N- (4-hydroxybutyl) benzamide (Compound 46)

¹ H-NMR (DMSO-d ₆ , 400 M
Hz) δ ppm: 1.40-1.70 (m, 4H),
3.20-3.50 (m, 4H), 3.80 (s, 3
H), 3.84 (s, 3H), 4.40 (t, J = 5.
1 Hz, 1 H), 6.75 (d, J = 15.5 Hz, 1
H), 6.99 (d, J = 8.4 Hz, 1H), 7.1
0-7.60 (m, 5H), 7.75 (dd, J = 7.
9, 1.4 Hz, 1 H), 8.55 (dd, J = 8.
4,1.0 Hz, 1H), 8.70-8.80 (m, 1
H), 11.49 (s, 1H)

(E) -N- (4-hydroxybutyl)-
2- (3,4,5-trimethoxycinnamoylamino)
Benzamide (compound 47)

¹ H-NMR (DMSO-d ₆ , 400 M
Hz) δ ppm: 1.40-1.70 (m, 4H),
3.20-3.50 (m, 4H), 3.70 (s, 3
H), 3.85 (s, 6H), 4.41 (t, J = 5.
1 Hz, 1 H), 6.85 (d, J = 15.5 Hz, 1
H), 7.08 (s, 2H), 7.10-7.60.
(M, 3H), 7.75 (dd, J = 7.9, 1.4H
z, 1H), 8.55 (dd, J = 8.4, 1.0H
z, 1H), 8.70-8.85 (m, 1H), 11.
52 (s, 1H)

(E) -2- (3-Ethoxy-4-methoxycycinnamoylamino) -N- (2-hydroxyethyl) benzamide (Compound 48)

¹ H-NMR (CDCl ₃ , 400 MH
z) δ ppm: 1.52 (t, J = 7.0 Hz, 3
H), 2.44 (t, J = 5.1 Hz, 1H), 3.5
5-3.70 (m, 2H), 3.80-4.00 (m,
5H), 4.17 (q, J = 7.0 Hz, 2H), 6.
44 (d, J = 15.5 Hz, 1H), 6.80-7.
20 (m, 5H), 7.40-7.55 (m, 2H),
7.67 (d, J = 15.5 Hz, 1H), 8.65 −
8.75 (m, 1H), 11.20 (s, 1H)

(E) -N- [2- [bis (2-hydroxyethyl) amino] ethyl] -2- (3,4-dimethoxycinnamoylamino) benzamide (Compound 49)

¹ H-NMR (CDCl ₃ , 400 MH
z) δ ppm: 2.45-3.65 (m, 12H),
3.92 (s, 3H), 3.96 (s, 3H), 6.4
6 (d, J = 15.5 Hz, 1H), 6.87 (d, J
= 8.3 Hz, 1H), 6.95-7.45 (m, 4
H), 7.54 (dd, J = 7.8, 1.2 Hz, 1
H), 7.67 (d, J = 15.5 Hz, 1H), 8.
05 (t, J = 5.3 Hz, 1H), 8.47 (d, J
= 8.3 Hz, 1H), 11.11 (s, 1H)

(E) -N- [2- [bis (2-hydroxyethyl) amino] ethyl] -2- (3,4,5-trimethoxycinnamoylamino) benzamide (compound 5
0)

¹ H-NMR (CDCl ₃ , 400 MH
z) δ ppm: 2.56 (t, J = 4.6 Hz, 4
H), 2.69 (t, J = 5.1 Hz, 2H), 3.4
5-3.65 (m, 6H), 3.89 (s, 3H),
3.92 (s, 6H), 6.51 (d, J = 15.5H)
z, 1H), 6.81 (s, 2H), 6.95-7.5.
(M, 2H), 7.55 (dd, J = 7.9, 1.3H
z, 1H), 7.65 (d, J = 15.5 Hz, 1
H), 8.04 (t, J = 5.3 Hz, 1H), 8.5
0 (dd, J = 8.3, 0.8 Hz, 1H), 11.1
8 (s, 1H)

Example 7 (E) -2- (3,4-Dimethoxycinnamoylamino) -N, N-dimethylbenzamide (Compound 51) (E) -2- (3,4-Dimethoxystyryl) -3, 1
-Benzoxazin-4-one (100 mg) and dimethylamine hydrochloride (80 mg) in pyridine (1 ml)
And triethylamine (0.13 ml), and 11
Stirred at 5 ° C. for 18 hours. After cooling, 2N hydrochloric acid was added to the reaction solution to make an acidic solution, which was extracted with ethyl acetate. The extract was washed with aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give (E) -2- (3,4-dimethoxycinnamoylamino) -N, N-dimethylbenzamide (95 mg). Obtained.

¹ H-NMR (CDCl ₃ , 400 MH
z) δ ppm: 3.0-3.25 (m, 6H);
92 (s, 3H), 3.95 (s, 3H), 6.44
(D, J = 15.5 Hz, 1H), 6.8-7.8
(M, 7H), 8.39 (d, J = 8.3 Hz, 1
H), 9.34 (s, 1H)

Example 8 The following compounds were synthesized in the same manner as in Example 7. (E) -2- (3,4-dimethoxycinnamoylamino) -N-methylbenzamide (compound 52)

¹ H-NMR (CDCl ₃ , 400 MH
z) δ ppm: 3.03 (d, J = 4.9 Hz, 3
H), 3.93 (s, 3H), 3.96 (s, 3H),
6.38 (brs, 1H), 6.49 (d, J = 15.
5Hz, 1H), 6.8-7.6 (m, 6H), 7.6
9 (d, J = 15.5 Hz, 1H), 8.74 (d, J
= 8.3 Hz, 1H), 11.30 (s, 1H)

(E) -N-cyclohexylmethyl-2-
(3,4-dimethoxycinnamoylamino) benzamide (compound 53)

¹ H-NMR (DMSO-d ₆ , 400M
Hz) δ ppm: 0.8-1.8 (m, 11H),
3.1-3.2 (m, 2H), 3.80 (s, 3H),
3.84 (s, 3H), 6.74 (d, J = 15.5H)
z, 1H), 6.9-7.8 (m, 7H), 8.52.
(D, J = 8.4 Hz, 1H), 8.7-8.8 (m,
1H), 11.44 (s, 1H)

(E) -2- (3,4-Dimethoxycinnamoylamino) -N-hydroxybenzamide (Compound 54)

¹ H-NMR (CDCl ₃ , 400 MH
z) δ ppm: 3.93 (s, 3H), 3.94
(S, 3H), 6.68 (d, J = 16.0 Hz, 1
H), 6.85-7.85 (m, 7H), 8.22 (d
d, J = 7.9, 1.5 Hz, 1H)

Example 9 (E) -2- (4-Dimethylaminocinnamoylamino) benzamide (Compound 55) (E) -2- (4-Dimethylaminostyryl) -3,1
-Benzoxazin-4-one (200 mg) was dissolved in a mixed solvent of methanol (5 ml) and methylene chloride (5 ml), and 28% aqueous ammonia (2 ml) was added thereto.
For 10 minutes. After the solvent was distilled off under reduced pressure, the obtained residue was washed with methylene chloride, and (E) -2- (4-dimethylaminocinnamoylamino) benzamide (24 m
g) was obtained.

¹ H-NMR (DMSO-d ₆ , 400M
Hz) δ ppm: 2.98 (s, 6H), 6.46
(D, J = 15.5 Hz, 1H), 6.72 (d, J =
8.8 Hz, 2H), 7.05-7.6 (m, 5H),
7.70 (brs, 1H), 7.80 (d, J = 6.9)
Hz, 1H), 8.27 (brs, 1H), 8.59
(D, J = 8.1 Hz, 1H), 11.79 (s, 1
H)

Example 10 (E) -2- (2-Carboxycinnamoylamino) benzamide (Compound 56) (E) -2- (2-Carboxystyryl) -3,1-benzoxazin-4-one (20 mg) ) 28% under ice cooling
The mixture was added to aqueous ammonia (1 ml) and stirred for 10 minutes. The reaction mixture was acidified with 1N hydrochloric acid, and the precipitate was collected by filtration and washed with water to obtain (E) -2- (2-carboxycinnamoylamino) benzamide (21 mg).

¹ H-NMR (DMSO-d ₆ , 400 M
Hz) δ ppm: 6.69 (d, J = 15.6 Hz,
1H), 7.45-7.95 (m, 8H), 8.25-
8.40 (m, 2H), 8.59 (d, J = 8.4H
z, 1H), 11.95 (s, 1H), 13.24 (b
rs, 1H)

Example 11 (E) -2- (3,5-Dimethoxy-4-hydroxycinnamoylamino) benzamide (Compound 57) (E) -4-Acetoxy-3,5-dimethoxycinnamic acid (70 mg) To a toluene (1 ml) solution was added thionyl chloride (38 μl) and one drop of N, N-dimethylformamide, and the mixture was stirred at 80 ° C. for 30 minutes. The reaction solution was concentrated under reduced pressure, pyridine (1 ml) and 2-aminobenzamide (43 mg) were added to the residue, and the mixture was stirred at 115 ° C for 10 minutes. The solvent was distilled off under reduced pressure, the residue was acidified with 2N hydrochloric acid, and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was separated and purified by silica gel column chromatography (elution solvent: ethyl acetate) to obtain (E) -2- (4-acetoxy-).
Methanol (1 ml) and potassium carbonate (36 m) were added to 3,5-dimethoxycinnamoylamino) benzamide.
g) was added and the mixture was stirred at room temperature for 5 minutes. After evaporating the solvent under reduced pressure, 2N hydrochloric acid was added to make the mixture acidic, and the mixture was extracted with ethyl acetate.
The extract was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was separated and purified by preparative thin-layer chromatography (developing solvent: ethyl acetate) to obtain (E) -2- (3,3).
5-dimethoxy-4-hydroxycinnamoylamino)
Benzamide (7 mg) was obtained.

¹ H-NMR (DMSO-d ₆ , 400M
Hz) δ ppm: 3.84 (s, 6H), 6.71
(D, J = 15.3 Hz, 1H), 7.04 (s, 2
H), 7.1-7.85 (m, 5H), 8.32 (br
s, 1H), 8.61 (d, J = 8.3Πz, 1H),
8.90 (brs, 1H), 11.78 (s, 1H)

Example 12 (E) -2- [3,5-Dimethoxy-4- (2-hydroxyethoxy) cinnamoylamino] benzamide (Compound 58) (E) -4- (2-acetoxyethoxy) -3 Thionyl chloride (40 μl) and a catalytic amount of N, N-dimethylformamide were added to a solution of 1,5-dimethoxycinnamic acid (57 mg) in toluene (1 ml), and the mixture was stirred at 80 ° C. for 1 hour.
The solvent was distilled off under reduced pressure. Pyridine (1 ml) and 2-aminobenzamide (25 mg) were added to the residue, and the mixture was added at 130 ° C.
After heating under reflux for 2 hours, the solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate, water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in methanol (0.5 ml) and potassium carbonate (17 m
g) and stirred at room temperature for 1 hour, 1N hydrochloric acid (0.5 ml) was added, and the solvent was distilled off under reduced pressure. After washing the residue with water and diethyl ether, preparative thin-layer chromatography (developing solvent: methylene chloride / diethyl ether /
(Methanol = 10/10/1) and purified by (E)-
2- [3,5-Dimethoxy-4- (2-hydroxyethoxy) cinnamoylamino] benzamide (5 mg) was obtained.

¹ H-NMR (CDCl ₃ + CD ₃ OD,
400 MHz) δ ppm: 3.7-3.85 (m, 2
H), 3.94 (s, 6H), 4.1-4.25 (m,
2H), 6.57 (d, J = 15.6 Hz, 1H),
6.86 (s, 2H), 7.1-7.6 (m, 2H),
7.61 (d, J = 15.6 Hz, 1H), 7.70
(Dd, J = 7.9, 1.4 Hz, 1H), 8.69
(Dd, J = 8.4, 0.9 Hz, 1H)

Example 13 (E) -2- [2- (3,4-Dimethoxycinnamoylamino) benzoylamino] benzoic acid (Compound 59) (E) -3,4-Dimethoxycinnamic acid chloride (84)
0.5 mg) and 2- (2-aminophenyl) -3,1
A suspension of -benzoxazin-4-one (884 mg) in pyridine (10 ml) was stirred at 120 ° C for 1.5 hours. The reaction solution was poured into water, and the precipitated solid was collected by filtration.
Washed sequentially with diethyl ether. This product (1.4
8 g) in 1N aqueous sodium hydroxide solution (10.4 m
l) and ethanol (20 ml),
For 30 minutes. The reaction solution was poured into ice water, the precipitated solid was collected by filtration, washed sequentially with water and diethyl ether,
(E) -2- [2- (3,4-Dimethoxycinnamoylamino) benzoylamino] benzoic acid (1.50 g) was obtained.

¹ H-NMR (DMSO-d ₆ , 400M
Hz) δ ppm: 3.79 (s, 3H), 3.82
(S, 3H), 6.77 (d, J = 15.6 Hz, 1
H), 6.98 (d, J = 8.4 Hz, 1H), 7.1
−7.4 (m, 4H), 7.5 to 7.75 (m, 3
H), 7.8-7.9 (m, 1H), 8.0-8.1.
(M, 1H), 8.33 (d, J = 8.3 Hz, 1
H), 8.58 (d, J = 8.3 Hz, 1H), 10.
73 (s, 1H), 11.89 (s, 1H), 12.5
-14.5 (br, 1H)

Example 14 (E) -2- (3,4-Dimethoxycinnamoylamino) -N- (2-dimethylaminoethyl) benzamide hydrochloride (Compound 60) (E) -2- (3,4- Dimethoxycinnamoylamino) -N- (2-dimethylaminoethyl) benzamide (100 mg) was dissolved in ethanol (1 ml), 1N hydrochloric acid (1 ml) was added, and the mixture was stirred at room temperature for 5 minutes. The reaction solution was concentrated under reduced pressure, and (E) -2- (3,4-dimethoxycinnamoylamino) -N- (2-dimethylaminoethyl)
Obtained benzamide hydrochloride (109 mg).

¹ H-NMR (CDCl ₃ , 400 MH
z) δ ppm: 2.88 (s, 3H), 2.90
(S, 3H), 3.25-3.35 (m, 2H), 3.
80-4.00 (m, 8H), 6.48 (d, J = 1
5.5 Hz, 1 H), 6.87 (d, J = 8.3 Hz,
1H), 7.05-7.20 (m, 3H), 7.45-
7.55 (m, 1H), 7.67 (d, J = 15.5H
z, 1H), 8.09 (dd, J = 8.0, 1.3H
z, 1H), 8.70-8.80 (m, 1H), 8.9
8 (t, J = 5.6 Hz, 1H), 11.60 (s, 1
H), 12.10-12.25 (br, 1H)

Example 15 The following compounds were synthesized in the same manner as in Example 14. (E) -N- (2-dimethylaminoethyl) -2- (4
-Ethoxy-3-methoxycinnamoylamino) benzamide hydrochloride (Compound 61)

¹ H-NMR (DMSO-d ₆ , 400
MHz) δ ppm: 1.33 (t, J = 7.0 Hz,
3H), 2.83 (s, 3H), 2.84 (s, 3
H), 3.2-3.75 (m, 4H), 3.82 (s,
3H), 4.05 (q, J = 7.0 Hz, 2H), 6.
74 (d, J = 15.5 Hz, 1H), 6.9-9.1
(M, 9H), 9.95-10.15 (br, 1H),
11.27 (s, 1H)

(E) -N- (2-dimethylaminoethyl) -2- (3,4,5-trimethoxycinnamoylamino) benzamide hydrochloride (Compound 62)

¹ H-NMR (DMSO-d ₆ , 400M
Hz) δ ppm: 2.83 (s, 3H), 2.84
(S, 3H), 3.15-3.75 (m, 7H), 3.
84 (s, 6H), 6.86 (d, J = 15.6 Hz,
1H), 7.0-7.25 (m, 3H), 7.5-9.
15 (m, 5H), 10.05-10.25 (br, 1
H), 11.30 (s, 1H)

Example 16 Test for Confirming Angiogenesis Inhibitory Effect Growth Inhibitory Effect of Human Capillary Endothelial Cells Culture of Human Capillary Endothelial Cells Normal Human Skin Capillary Endothelial Cells (Cell System)
ms Corporation) in an endothelial cell culture medium (MVE medium, Cell Systems Corpo)
(Ration Co., Ltd.). During the logarithmic growth phase, the culture medium is removed and a phosphate buffered saline solution (PBS
(-)) Was gently added to wash the cells. Then the PB
Except for S (-), 0.1% EDTA containing 0.02%.
A 25% trypsin solution was appropriately added, and the state of the cells was observed with a phase contrast microscope. While the cells were becoming spherical, an equal volume of MVE medium was added to the trypsin solution to stop the action of trypsin. The cells were detached from the culture plate by pipetting with a narrow Pasteur pipette. The cell suspension was transferred to a Spitz tube, the medium was added, and pipetting was performed vigorously about 20 times with a Pasteur pipette, followed by centrifugation at 100 to 110 G for 1 minute. Discard the supernatant,
A new medium was added, and pipetting was performed with a Pasteur pipette to prepare a cell suspension. A part of the cell suspension was taken, and the number of viable cells was counted with a phase contrast microscope using a hemocytometer. The cell concentration was adjusted to 2.5 × 10 ^{4 to} 5 × 10 ⁴ cells / ml.

Preparation of Reagents All of the reagents were dissolved in dimethyl sulfoxide (DMSO) and diluted with a vascular endothelial cell culture medium to a final concentration of a predetermined concentration. The final concentration of DMSO was 0.5%.

Experimental Procedure According to the following method 1 or 2, the inhibitory effect of the compound represented by formula (I) on the proliferation of human capillary endothelial cells was examined. (Method 1) Collagen-coated 6-well plate (Toy
obo EngineeringCo. Ltd. Was added at 37 ° C., 5% carbon dioxide-9.
The cells were cultured under 5% gas phase. After one day of culture, remove the culture solution,
After washing the cells with PBS (-), vascular endothelial cell culture medium containing various concentrations of the test substance was added, and the cells were further cultured for 2 days. After completion of the culture, the culture solution is removed, and PBS (-)
After washing the cells with, 1 ml of a 0.25% trypsin solution containing 0.02% EDTA was added. After peeling the cells from the plate by pipetting with a Pasteur pipette,
The number of viable cells was measured using a hemocytometer. In addition, the growth inhibitory activity of the test substance was represented by the concentration (IC ₅₀ ) showing 50% inhibition with respect to the drug-untreated group.

[Results] As shown in Table 1 below, the compound of the above general formula (I) markedly suppressed the proliferation of human microvascular endothelial cells.

[0259]

[Table 1]

(Method 2) Collagen-coated 96-well plate (Toyobo Engineering C)
o. Ltd. 200 μl of each well cell suspension was added and cultured at 37 ° C. under 5% CO 2 -95% gas phase.
One day after the culture, the culture was replaced with 200 μl of a vascular endothelial cell culture medium containing 100 μM of the test substance, and the cells were cultured.
After 4 days of culturing, cell proliferation measurement reagent Alamar Blu
e was added to each well in an amount of 20 μl, and the cells were further cultured for 4 hours. The absorbance at 620 nm and 540 nm was measured with an immunoreader to calculate the number of cells. In addition, the growth inhibitory activity of the test substance was represented by the inhibition rate (%) with respect to the drug-untreated group.

[Results] As shown in Table 2 below, the compound of the above general formula (I) markedly inhibited the proliferation of human microvascular endothelial cells.

[0262]

[Table 2]

Example 17 Acute toxicity test Male ICR mice were fasted for 4 hours and suspended in 0.5% sodium carboxymethylcellulose (E) -2-
(3,4-dimethoxycinnamoylamino) benzamide 300, 1000, 2000 mg / kg or (E)-
2- (3,4,5-trimethoxycinnamoylamino)
When benzamide 300 or 1000 mg / kg was orally administered and the presence or absence of death was examined, no death cases were observed in all administration groups.

Formulation Example 1 Fine granule 100 mg Lactose 600 mg Corn starch 265 mg Hydroxypropyl cellulose 30 mg Calcium stearate 5 mg (Total 1000 mg)

Formulation Example 2 Capsule Active drug 100 mg Crystalline cellulose 50 mg Carmellose calcium 13 mg Hydroxypropyl cellulose 4 mg Calcium stearate 3 mg (Total 170 mg)

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification symbol FI // C07C 237/42 C07C 237/42 (72) Inventor Yoshinori Nonaka 491-2-2 Toyoshina, Toyoshina-cho, Toshina-cho, Minamiazumi-gun, Nagano Fragrance Hana Mizuki C-202 (72) Inventor Koji Kamata 433-1 Shimauchi, Oaza, Matsumoto City, Nagano Prefecture Fragrance Melody A101 (72) Inventor Nobuhiko Fukuro, 2105-387 Ariake, Ajiaki, Hotaka-cho, Minamiazumi-gun, Nagano 205 No. 205, Corp.

Claims (1)

[Claims] 1. A compound of the general formula [Wherein R ¹ is a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a hydroxy lower alkoxy group, a cycloalkyl alkoxy group, an aralkyloxy group, a lower acyl group, a nitro group, a cyano group, a lower alkyl group. Is an amino group, a carboxyl group, a lower alkoxycarbonyl group or a lower alkylsulfonyl group which may be mono- or di-substituted, and R ² and R ³ may be the same or different and each represents a hydrogen atom or a lower alkoxy group. ^{May be} present, or may be taken together to form a lower alkylene group via an oxygen atom, and B is represented by the general formula -N (R ⁴ ) (R ⁵ ) (wherein R ⁴ and R ⁵ are the same or different. May be
Each a hydrogen atom, a lower alkyl group, a group represented by a cycloalkyl group or an aralkyl group), the formula _{-NH- (CH 2) n -A-} R 6 [A in the formula is a single bond, general formula A group represented by —O— (CH ₂ ) _m — (where m is an integer of 2 to 6) or a general formula —N (R ⁷ ) (CH ₂ ) _p − (wherein R ⁷ is A hydrogen atom or a lower alkyl group which may have an amino group which may be mono- or di-substituted by a lower alkyl group as a substituent;
R ⁶ is an amino group which may be mono- or di-substituted by a hydroxyl group or a lower alkyl group, and n is an integer of 2 to 6). Or an arylamino group or a hydroxyamino group which may have a carboxyl group as a substituent], or a pharmacologically acceptable salt thereof as an active ingredient. An angiogenesis inhibitor characterized by containing